Process for the preparation of 6-(perfluoroalkyl) uracil compounds from 2-(N,N-disubstituted) amino-4-(perfluoroalkyl)-1,3-oxazin-6-one compounds

Abstract

An improved process for the preparation of 6-(perfluoroalkyl)uracil compounds having the structural formula I ##STR1## from 2-(N,N-disubstituted)amino-4-(perfluoroalkyl)-1,3-oxazin-6-one compounds having the structural formula II ##STR2##

We claim: 
     
       1. A process for the preparation of a 6-(perfluoroalkyl)uracil compound having the structural formula I ##STR191## wherein n is an integer of 1,2,3,4,5 or 6; Z is hydrogen or C 1  -C 6  alkyl; and   Q is a C 1  -C 6  alkyl group or ##STR192## where G is CH 2  or a bond;   G 1  is CX 5  or N;   G 2  is CX 4  or N;   X 1  is hydrogen, halogen or a C 1  -C 6  alkyl group optionally substituted with one epoxy group,   X 2  is hydrogen, halogen, NRR 1 , CO 2  R 2 , C(O)R 3 , OR 4 , SO 2  R 5 , SO 2  NR 6  R 7 , C(R 8 )(OR 9 ) 2 , C(R 10 )═NOR 11 , C(R 12 )═C(R 13 )--C(OR 14 )═NOR 15 , CH 2  O--NCO 2  R 16 , 1,3-dioxolane optionally substituted with one C 1  -C 6  alkoxy group or one or two C 1  -C 4  alkyl groups,     1,3-dioxolinone optionally substituted with one C 1  - 6  alkoxy group or one or two C 1  -C 4  alkyl groups, or   C 1  -C 4  alkyl optionally substituted with one CO 2  R 2  group and one halogen atom, and       X 3  is hydrogen, halogen, C 1  -C 4  haloalkyl, CO 2  R 17 , cyano, C 1  -C 4  haloalkoxy, OR 18  or C 1  -C 4  alkyl, or when X 1  and X 2  are taken together with the atoms to which they are attached, they may form a five- or six-membered ring wherein X 1  X 2  or X 2  X 1  is represented by: --OC(R 20 )(R 21 )O--, --CH 2  S(O) p  N(R 22 )--, --SC(R 23 )═N--, --CH═CH--CH(R 11 )O--, --OC(O)N--, --SC(R 24 )═N--, --ON(R 25 )C(O)--, --OC(CO 2  R 26 )═C(R 27 )--, --NC(R 28 )═C(SR 29 )--, --CH═C(CO 2  R 30 )O--, --CH 2  CH(R 31 )O-- or --OC(R 32 )(R 33 )C(O)--, or     when X 2  and X 3  are taken together with the atoms to which they are attached, they may form a five- or six-membered ring wherein X 2  X 3  or X 3  X 2  is represented by: --NC(R 34 )═NC(S)--, --N(R 35 )N═C(R 36 )--, --N(R 37 )C(R 38 )═N--, --N(R 38 )C(O)CH 2  O--, --N(R 39 )C(O)CH═CH--, --S--N═C(R 40 )--, --O--N═C(R 41 )--, --N═N--N(R 42 )--, --C(R 43 )(R 44 )C(O)N(R 45 )-- or --N(R 46 )C(O)C(R 47 )(R 48 )--,       X 4  is hydrogen, halogen or OR 19  ;   X 5  is hydrogen or halogen;   R, R 56 , R 64 , R 69 , R 70 , R 77  and R 91  are each independently hydrogen, SO 2  R 49 , C 1  -C 4  alkyl, C 3  -C 7  cycloalkyl, C 3  -C 6  alkenyl, C 3  -C 6  alkynyl, phenyl or benzyl;   R 1  is hydrogen, SO 2  R 50 , C(O)R 51 , amino or C 1  -C 4  alkyl optionally substituted with CO 2  R 52  or C(O)R 53  ;   R 2 , R 16 , R 17 , R 26 , R 30 , R 68 , R 75 , R 76 , R 82  and R 88  are each independently hydrogen, C 1  -C 8  haloalkyl, C 3  -C 8  alkenyl, C 3  -C 6  alkynyl, phenyl, benzyl, furfuryl, pyridyl, thienyl, C 1  -C 8  alkyl optionally substituted with CO 2  R 54 , morpholine or C(O)R 55 , or   an alkali metal, an alkaline earth metal, ammonium or organic ammonium cation;     R 3 , R 66 , R 67 , R 81 , R 85  and R 89  are each independently hydrogen, C 1  -C 6  alkyl, C 3  -C 6  alkenyl, C 3  -C 6  alkynyl, NR 56  R 57 , phenyl or benzyl;   R 4 , R 18 , R 19  and R 65  are each independently hydrogen, C 1  -C 6  alkyl, C 3  -C 6  alkenyl, C 3  -C 6  alkynyl, C 1  -C 4  haloalkyl, C(O)R 58 , C(S)R 59  or benzyl;   R 5  and R 72  are each independently C 1  -C 6  alkyl, C 1  -C 6  haloalkyl, NR 60  R 61 , imidazole or indazole;   R 6 , R 11 , R 12 , R 14 , R 15 , R 20 , R 21 , R 22 , R 25 , R 28 , R 29 , R 31 , R 32 , R 33 , R 35 , R 45 , R 46 , R 63  and R 80  are each independently hydrogen or C 1  -C 4  alkyl;   R 7  is hydrogen, C 3  -C 6  alkenyl, C 3  -C 6  alkynyl, benzyl, or C 1  -C 4  alkyl optionally substituted with cyano or C(O)R 62  ;     R 8  and R 27  are each independently hydrogen, C 1  -C 4  alkyl or C 1  -C 4  alkoxy;   R 9  and R 90  are each independently C 1  -C 6  alkyl;   R 10  is hydrogen, C 1  -C 6  alkyl, phenyl or benzyl;   R 13 , R 24  and R 36  are each independently hydrogen, C 1  -C 6  alkyl or halogen;   R 23  is hydrogen or NR 63  R 64  ;   R 34  is hydrogen, C 1  -C 4  alkyl or C 1  -C 4  haloalkyl;   R 37  is hydrogen, C 1  -C 4  alkyl or C 2  -C 8  alkoxyalkyl;   R 38  and R 39  are each independently hydrogen, C 1  -C 4  alkyl, C 1  -C 4  haloalkyl, C 3  -C 6  alkenyl or C 3  -C 6  alkynyl;   R 40 , R 41  and R 42  are each independently hydrogen, halogen, cyano, OR 65 , C(O)R 66 , C(S)R 67 , CO 2  R 68 , C(═NOR 69 ), a C 1  -C 8  alkyl, C 3  -C 7  cycloalkyl, C 2  -C 8  alkenyl or C 2  -C 8  alkynyl group, wherein each group is optionally substituted with any combination of one to six halogen atoms, one to three C 1  -C 10  alkoxy groups, one or two C 1  -C 6  haloalkoxy groups, one or two NR 70  R 71  groups, one or two S(O) q  R 72  groups, one or two cyano groups, one or two C 3  -C 7  cycloalkyl groups, one OSO 2  R 73  group, one or two C(O)R 74  groups, one or two CO 2  R 75  groups, one or two C(O)SR 76  groups, one or two C(O)NR 77  R 78  groups, one to three OR 79  groups, one or two P(O)(OR 80 ) 2  groups, one 1,3-dioxolane optionally substituted with one to three C 1  -C 4  alkyl groups, or one 1,3-dioxane optionally substituted with one to three C 1  -C 4  alkyl groups, or   phenyl or benzyl optionally substituted with any combination of one to three halogen atoms, one to three C 1  -C 6  alkyl groups, one to three C 1  -C 6  alkoxy groups, one C 3  -C 7  cycloalkyl group, one C 1  -C 4  haloalkyl group, one C 1  -C 4  alkylthio group, one cyano group, one nitro group, one C(O)R 81  group, one CO 2  R 82  group, one OR 83  group, one SR 84  group, one C 1  -C 6  alkoxymethyl group, one hydroxymethyl group, one C 3  -C 8  alkenyloxymethyl group, or one C 1  -C 8  haloalkoxymethyl group;     R 43 , R 44 , R 47  and R 48  are each independently hydrogen, C 1  -C 4  alkyl, C 1  -C 4  haloalkyl, C 3  -C 6  alkenyl, C 3  -C 6  alkynyl or C 3  -C 7  cycloalkyl, or R 43  and R 44  or R 47  and R 48  may be taken together with the atom to which they are attached to form a C 3  -C 7  cycloalkyl group;   R 49 , R 50  and R 86  are each independently C 1  -C 6  alkyl, NR 93  R 94 , C 1  -C 4  haloalkyl, C 3  -C 6  alkenyl, C 3  -C 6  alkynyl or benzyl;   R 51 , R 52 , R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 60 , R 61 , R 62 , R 71 , R 73 , R 74 , R 78 , R 87  and R 92  are each independently hydrogen, C 1  -C 6  alkyl, C 3  -C 7  cycloalkyl, C 1  -C 6  haloalkyl, C 3  -C 6  alkenyl, C 3  -C 6  alkynyl, phenyl or benzyl;   R 79 , R 83  and R 84  are each independently hydrogen, C(O)R 85 , SO 2  R 86 , C 1  -C 6  haloalkyl, C 2  -C 6  alkenyl, C 5  -C 8  cycloalkenyl, C 2  -C 6  alkynyl, phenyl, benzyl, or C 1  -C 10  alkyl optionally substituted with one hydroxyl, benzyloxy, OC(O)R 87 , C 1  -C 6  alkoxy, CO 2  R 88 , C(O)R 89 , C(OR 90 ) 2 , C(O)NR 91  R 92  or cyano group;     R 93  and R 94  are each independently hydrogen, C 1  -C 4  haloalkyl, C 2  -C 6  alkenyl, C 3  -C 8  cycloalkyl, C 1  -C 8  alkyl optionally substituted with one or two C 1  -C 4  alkoxy groups or one cyanoalkyl group, or   benzyl or phenyl optionally substituted with any combination of one to three halogen atoms, one to three C 1  -C 4  alkyl groups, one to three C 1  -C 4  haloalkyl groups, one to three C 1  -C 4  alkoxy groups, one to three C 1  -C 4  haloalkoxy groups, one cyano group or one nitro group, and   when R 93  and R 94  are taken together with the nitrogen atom to which they are attached, they form a 5- to 12-membered monocyclic or fused bicyclic, heterocyclic ring optionally substituted with one or more groups independently selected from halogen, cyano, nitro, amino, hydroxyl, C 1  -C 4  alkyl, C 1  -C 4  haloalkyl, C 1  -C 4  alkoxy, C 1  -C 4  haloalkoxy and C 1  -C 4  haloalkylsulfonyl groups; p and q are each independently 0, 1 or 2;     which process comprises: (a) reacting a 2-(N,N-disubstituted)amino-4-(perfluoroalkyl)-1,3-oxazin-6-one compound having the structural formula II ##STR193## wherein Z 1  and Z 2  are each independently C 1  -C 8  alkyl or Z 1  and Z 2  may be taken together with the atom to which they are attached to form a 4- to 7-membered ring wherein Z 1  Z 2  is represented by --(CH 2 ) 2  O(CH 2 ) 2  -- or --(CH 2 ) m  -- where m is an integer of 3, 4, 5 or 6; and     n is as described above,   with an amine compound having the structural formula III   QNH.sub.2                                                  (III)       wherein Q is as described above, in the presence of an acid or base to form the 6-(perfluoroalkyl)uracil compound of formula I wherein Z is hydrogen; and (b) optionally alkylating the formula I compound wherein Z is hydrogen to form a formula I compound wherein Z is C 1  -C 6  alkyl.     
     
     
       2. The process according to claim 1 wherein the reaction of step (a) occurs in the presence of an acid. 
     
     
       3. The process according to claim 2 wherein the acid is selected from the group consisting of a C 1  -C 6  alkanoic acid, hydrochloric acid, sulfuric acid and phosphoric acid. 
     
     
       4. The process according to claim 2 wherein the acid is selected from the group consisting of acetic acid and propionic acid. 
     
     
       5. The process according to claim 1 wherein the base is selected from the group consisting of a tri-(C 1  -C 6  alkyl)amine, a heterocyclic tertiary amine and an alkali metal C 1  -C 6  alkoxide. 
     
     
       6. The process according to claim 5 wherein the base is selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,5-diazabicyclo-[4.3.0]non-5-ene. 
     
     
       7. The process according to claim 1 wherein the 2-(N,N-disubstituted)amino-4-(perfluoroalkyl)-1,3-oxazin-6-one compound is reacted with the amine compound in the presence of a solvent. 
     
     
       8. The process according to claim 7 wherein the solvent is selected from the group consisting of a carboxylic acid amide, a dialkyl sulfoxide, an aromatic hydrocarbon, a halogenated aromatic hydrocarbon, an aliphatic hydrocarbon, a halogenated aliphatic hydrocarbon, an alkanoic acid, a ketone, an ether, a nitrile and water and mixtures thereof. 
     
     
       9. The process according to claim 1 wherein the 2-(N,N-disubstituted)amino-4-(perfluoroalkyl)-1,3-oxazin-6-one compound is reacted with the amine compound at a temperature of about 20° C. to 150° C. 
     
     
       10. The process according to claim 1 wherein step (b) comprises reacting the formula I compound wherein Z is hydrogen with an alkyl halide having the structural formula IV or a dialkylsulfate ester having the structural formula V ##STR194## wherein X is chlorine, bromine or iodine, and Z is C 1  -C 6  alkyl in the presence of a base. 
     
     
       11. The process according to claim 1 wherein n is 1;   Z is hydrogen or C 1  -C 4  alkyl;   and Z 1  and Z 2  are each independently C 1  -C 6  alkyl.   
     
     
       12. The process according to claim 11 wherein Z is hydrogen or methyl;   X 1  is hydrogen, fluorine or C 1  -C 3  alkyl optionally substituted with one epoxy group; or when X 1  and X 2  are taken together with the atoms to which they are attached, they may form a five- or six-membered ring wherein X 1  X 2  or X 2  X 1  is represented by: --OC(R 20 )(R 21 )O--, --CH 2  S(O) p  N(R 22 )--, --SC(R 23 )═N--, --CH═CH--CH(R 11 )O--, --OC(O)N--, --SC(R 24 )═N--, --ON(R 25 )C(O)--, --OC(CO 2  R 26 )═CH--, --NC(R 28 )═C(SR 29 )--, --CH═C(CO 2  R 30 )O--, --CH 2  CH(R 31 )O-- or --OC(R 32 )(R 33 )C(O)--;       R, R 64 , R 69  and R 77  are each independently hydrogen, SO 2  R 49  or C 1  -C 4  alkyl;   R 2 , R 16 , R 17 , R 26 , R 30 , R 68 , R 75 , R 76 , R 82  and R 88  are each independently hydrogen, C 3  -C 6  alkenyl or C 1  -C 4  alkyl optionally substituted with CO 2  R 54 , morpholine or C(O)R 55  ;   R 3 , R 66 , R 67 , R 85  and R 89  are each independently hydrogen, C 1  -C 4  alkyl or NR 56  R 57  ;   R 4 , R 18  and R 19  are each independently hydrogen, C 1  -C 4  alkyl, C 1  -C 4  haloalkyl, C(O)R 58 , C 3  -C 4  alkenyl or C 3  -C 4  alkynyl;   R 56  is SO 2  R 49  ;   R 57  is hydrogen or C 1  -C 4  alkyl;   R 5  and R 72  are each independently NR 60  R 61  or indazole;   R 6 , R 11 , R 12 , R 14 , R 15 , R 20 , R 21 , R 22 , R 25 , R 28 , R 29 , R 31 , R 32 , R 33 , R 35 , R 45 , R 46  and R 80  are each independently hydrogen or methyl;   R 7  is C 1  -C 4  alkyl optionally substituted with cyano or C(O)R 62  ;   R 8  is hydrogen or C 1  -C 4  alkoxy;   R 9  and R 90  are each independently C 1  -C 4  alkyl;   R 10  is hydrogen or C 1  -C 3  alkyl;   R 13 , R 24  and R 36  are each independently hydrogen or chlorine;   R 23  is NR 63  R 64  ;   R 34  is C 1  -C 3  haloalkyl;   R 37  is C 2  -C 4  alkoxyalkyl;   R 38  and R 39  are each independently C 1  -C 3  haloalkyl, C 1  -C 3  alkyl or propargyl;   R 40 , R 41 , and R 42  are each independently hydrogen, C(O)R 66 , C(S) R 67 , CO 2  R 68 , C(═NOR 69 ), C 1  -C 3  alkyl optionally substituted with any combination of one or two halogen atoms, one or two C 1  -C 3  alkoxy groups, one or two C 1  -C 3  haloalkoxy groups, one SO 2  R 72  group, one or two cyano groups, one C 3  -C 5  cycloalkyl group, one OSO 2  R 73  group, one C(O)R 74  group, one CO 2  R 75  group, one C(O)SR 76  group, one C(O)NR 77  R 78  group, one to two OR 79  groups, one P(O)(OR 80 ) 2  group, one 1,3-dioxolane group or one 1,3-dioxane group, or   phenyl optionally substituted with any combination of one halogen atom, one or two methyl groups, one methoxy group, one halomethyl group or one OR 83  group;     R 43 , R 44 , R 47  and R 48  are each independently hydrogen or methyl, or R 43  and R 44  or R 47  and R 48  may be taken together with the atom to which they are attached to form a cyclopropyl group;   R 49 , R 50  and R 86  are each independently C 1  -C 4  alkyl or NR 93  R 94  ;   R 51 , R 52 , R 53 , R 54 , R 55 , R 58 , R 60 , R 61 , R 62 , R 73 , R 74 , R 78  and R 87     are each independently hydrogen, C 1  -C 4  alkyl or C 1  -C 4  haloalkyl;   R 79  and R 83  are each independently hydrogen, C(O)R 85 , SO 2  R 86 , C 1  -C 4  haloalkyl, C 3  -C 4  alkenyl or C 1  -C 3  alkyl substituted with one OC(O)R 87 , CO 2  R 88 , C(O)R 89 , C(OR 90 ) 2  or cyano group;     R 93  and R 94  are each independently hydrogen or C 1  -C 8  alkyl;   p is 0, 1 or 2; and   Z 1  and Z 2  are the same and represent methyl or ethyl.   
     
     
       13. The process according to claim 1 for the preparation of a 6-(trifluoromethyl)uracil compound having the structural formula VI ##STR195## wherein Z is hydrogen or methyl; X 5  is hydrogen or halogen;   R 40  is hydrogen, C(O)R 66 , C(S)R 67 , CO 2  R 68 , C 1  -C 3  alkyl optionally substituted with any combination of one or two halogen atoms, one or two C 1  -C 3  alkoxy groups, one or two C 1  -C 3  haloalkoxy groups, one SO 2  R 72  group, one or two cyano groups, one C 3  -C 5  cycloalkyl group, one OSO 2  R 73  group, one or two OR 79  groups, one P(O)(OR 80 ) 2  group, one 1,3-dioxolane group or one 1,3-dioxane group, or   phenyl optionally substituted with any combination of one halogen atom, one or two methyl groups, one methoxy group, one halomethyl group or one OR 83  group;     R 66 , R 67 , R 85  and R 89  are each independently hydrogen, C 1  -C 4  alkyl or NR 56  R 57  ;   R 56  is SO 2  R 49  ;   R 57  is hydrogen or C 1  -C 4  alkyl;   R 49  and R 86  are each independently C 1  -C 4  alkyl or NR 93  R 94  ;   R 93  and R 94  are each independently hydrogen or C 1  -C 8  alkyl;   R 68  and R 88  are each independently hydrogen, C 3  -C 6  alkenyl or C 1  -C 4  alkyl optionally substituted with CO 2  R 54 , morpholine or C(O)R 55  ;     R 54 , R 55 , R 60 , R 61 , R 73  and R 87  are each independently hydrogen, C 1  -C 4  alkyl or C 1  -C 4  haloalkyl;   R 72  is NR 60  R 61  or indazole;   R 79  and R 83  are each independently hydrogen C(O)R 85 , SO 2  R 86 , C 1  -C 4  haloalkyl, C 3  -C 4  alkenyl or C 1  -C 3  alkyl substituted with one OC(O)R 87 , CO 2  R 88 , C(O)R 89 , C(OR 90 ) 2  or cyano group;     R 80  is hydrogen or methyl; and   R 90  is C 1  -C 4  alkyl.